Multiple Sclerosis
Multiple sclerosis (“MS”) is a demyelinating disease characterized by inflammation in the brain and spinal cord. MS is the most common human autoimmune disease involving the nervous system. In the United States, approximately 250,000 individuals suffer from MS. In MS, cells of the immune system invade and destroy myelin, the fatty material that insulates nerves in the brain and spinal cord. Other CNS cells produce a hardened sclerotic lesion (plaque) around the multiple demyelinated sites. Neurologic findings suggest lesions in separate areas of the CNS that occur at different times.
A typical presentation of MS involves an initial course, running for several years to more than a decade, manifest by episodes of relapse followed by remission. Relapses often follow an episode of a viral infection of the upper respiratory system or gastrointestinal tract. In about one third of MS patients, this disease evolves into a progressive course termed “secondary progressive MS.” In a minority of patients, progressive neurologic deterioration without remission occurs from the onset of disease, and this is called “primary progressive MS.” The pathophysiologic and genetic causes underlying primary versus secondary progressive MS remain unclear.
Clinical problems observed in MS patients may include disturbances in visual acuity, sometimes culminating in blindness; double vision; motor disturbances affecting walking and use of the hands; uncoordination; bowel and bladder incontinence; spasticity; and sensory disturbances including loss of touch, pain, temperature and proprioception. The pathology of MS lies entirely in the central nervous system and is characterized by a classic picture of inflammation surrounding venules and extending into the myelin sheath.
Immune responses to various components of the myelin sheath have been detected in MS patients. These components include myelin basic protein (“MBP”), proteolipid (“PLP”), transaldolase and 2′,3′ cyclic nucleotide 3′phosphodiesterases (“CNP”), as well as two members of the immunoglobulin supergene family found in the myelin sheath, i.e., myelin oligodendroglial glycoprotein (“MOG”) and myelin-associated glycoprotein (“MAG”) (11). In addition, some inducible heat shock proteins, including crystallin-B, can be detected in glial cells in MS lesions and can stimulate an immune response in MS patients. The major T and B cell response in the central nervous systems of the roughly two thirds of MS patients who are HLA DR2 is directed to a region between residues 84 and 103 of MBP (14, 18).
Osteopontin
Osteopontin (“OPN”), also called early T cell activation gene-1, is a human protein whose primary structure has been characterized (25). OPN is a pleiotropic protein having a conserved RGD binding motif, and when produced by osteoblasts is involved in the anchoring of osteoclasts to the mineral of bone matrix. Expression of osteopontin in bone tissue is stimulated by 1-alpha-1,25-dihydroxyvitamin D3. Osteopontin also provides the protein matrix for urinary stones.
Osteopontin also plays roles in inflammation and in immunity to infectious diseases (29). Osteopontin costimulates T cell proliferation (8), and is classified as a Th1 cytokine, due to its ability to enhance IFN-gamma and IL-12 production, and to diminish IL-10 (32). It has been shown that osteopontin expression in rat aortic smooth muscle cells is inhibited by NK-104, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor.